A growing body of research has shown that the stroma plays a significant role in the maintenance and growth of carcinomas, but little is known about the different types of stroma that exist in tumors. Moreover, as the stromal cells within the tumor are thought to be "normal" and less genetically labile than the neoplastic cells, development of acquired resistance to therapy is thought to be less likely and as such, the tumor stroma may be an excellent target for directed therapy. Tumor stroma contains a variety of mesenchymal cell types that include fibroblasts, myofibroblasts, endothelial cells, and adipocytes. The expression profiles of these lineages are only partially known and it is likely that several currently unrecognized subtypes of these cells exist. We hypothesize that within a particular group of tumors (e.g. breast carcinoma) there exist distinct types of stroma that affect tumor growth in different ways. We further hypothesize that soft tissue tumors (STTs), thought to be derived from different stromal precursors, could function as discovery tools for the various stroma types. Soft tissue tumors (including the malignant variants called sarcomas) are derived from a wide variety of normal connective tissue cells and can be thought of as clonal outgrowths of different subtypes of mesenchymal cells such as fibroblasts and myofibroblasts, and other, as yet undiscovered, stromal components. We propose to use STTs as "discovery tools" in a genome-wide search to discover groups of novel markers that identify distinct types of tumor stroma and that recognize the normal connective tissue counterparts from which these types of stroma are derived. By identifying subsets of genes that distinguish different STT, our project will examine how these gene sets can differentiate between carcinomas with distinct stroma types. In two separate studies we have shown that this is feasible and that in fact the different stroma types are associated with different clinical outcomes. In the proposed project, we will perform gene expression profiling on additional STTs to discover further new types of carcinoma stroma. Subsequently, we will verify and extend our findings on tissue microarrays containing hundreds of specimens of several carcinomas from patients with known clinical follow-up. Finally, we will identify epithelial-stromal gene-pairs involved in the "cross-talk" between cancer and stromal cells. This grant proposal aims to expand our understanding of stromal responses to cancer and, by finding new genes and pathways involved in this response, identify new targets for tumor microenvironment-targeted therapy. In addition to their use as prognostic markers, we believe that potential therapeutic targets may also be discovered in the group of genes, especially those involved in "cross-talk" between cancer and stromal cells. Our studies will also help identify which subsets of cancers would respond to these stroma-targeted therapies. The fact that different carcinomas share expression of these targets would mean that large groups of patients suffering from a variety of tumors could benefit. PUBLIC HEALTH RELEVANCE: This grant proposal aims to expand our understanding of stromal responses to cancer and, by finding new genes and pathways involved in this response, identify new targets for tumor microenvironment-targeted therapy. In addition to their use as prognostic markers, we believe that potential therapeutic targets may also be discovered in the group of genes, especially those involved in "cross-talk" between cancer and stromal cells. The fact that different carcinomas share expression of these targets would mean that large groups of patients suffering from a variety of tumors could benefit.